AT-101 Enhances the Antitumor Activity of Lenalidomide in Patients with Multiple Myeloma

Abstract

Bcl-2 and Mcl-1 proteins play a role in multiple myeloma (MM) cell survival, for which targeted inhibitors are being developed. AT-101 is an oral drug, which disrupts Bcl-2 and Mcl-1 function, impedes mitochondrial bioenergetic processes and induces apoptosis in MM cells. When combined with lenalidomide and dexamethasone (Rd), AT-101 significantly reduced tumor burden in an in vivo xenograft model of MM. These data provided rationale for a phase I/II study to establish the effective dose of AT-101 in combination with Rd (ARd regimen) in relapsed/refractory MM. A total of 10 patients were enrolled, most with high-risk cytogenetics (80%) and prior stem cell transplant (70%). Three patients were lenalidomide-refractory, 2 were bortezomib-refractory and 3 were daratumumab-refractory. The ARd combination was well tolerated with most common grade 3/4 adverse events being cytopenia’s. The overall response rate was 40% and clinical benefit rate was 90%. The median progression free survival was 14.9 months (95% CI 7.1-NE). Patients responsive to ARd showed a decrease in Bcl-2:Bim or Mcl-1:Noxa protein complexes, increased CD8+ T and NK cells and depletion of T and B-regulatory cells. The ARd regimen demonstrated an acceptable safety profile and promising efficacy in patients with relapsed/refractory MM prompting further investigation in additional patients.

Advances in mitophagy and mitochondrial apoptosis pathway-related drugs in glioblastoma treatment

“…Therefore, the development of single-isomer pharmaceutical preparations can avoid potential adverse reactions. Thus far, AT-101 has been considered a promising anti-cancer drug for the treatment of various tumors, including multiple myeloma (Ailawadhi et al, 2023), adrenal cortical carcinoma (Yurekli et al, 2018), esophagus cancer (Que et al, 2019), breast cancer (Bulut et al, 2020), lung cancer (Ahmad et al, 2021;Renner et al, 2022), and prostate cancer (Aktepe and Yukselten, 2022).…”

Platinum-Based Mcl-1 Inhibitor Targeting Mitochondria Achieves Enhanced Antitumor Activity as a Single Agent or in Combination with ABT-199

“…Studies showed that cancer cells with elevated Mcl-1 levels are resistant to the selective Bcl-2 inhibitor ABT-199 (venetoclax) and its derivatives and therefore limit their clinical application . Inhibition of Mcl-1 with small molecular agents enhances the antitumor activity of other anticancer agents in various cancer cell lines, such as acute myeloid leukemia cells, − non-Hodgkin’s lymphoma cells, T-cell acute lymphoblastic leukemia (T-ALL) cells, and multiple myeloma. , …”

“…11 Inhibition of Mcl-1 with small molecular agents enhances the antitumor activity of other anticancer agents in various cancer cell lines, 12 such as acute myeloid leukemia cells, 13−15 non-Hodgkin's lymphoma cells, 16 T-cell acute lymphoblastic leukemia (T-ALL) cells, 17 and multiple myeloma. 18,19 Mcl-1 has become an important drug target for multiple cancers, and some potent small molecular Mcl-1 inhibitors have been discovered. 20,21 However, targeting Mcl-1 confronts many difficulties for the development of drug-like inhibitors: First, most reported Mcl-1 inhibitors lack convincing antitumor activity, likely due to their poor pharmaceutical properties, such as low membrane permeability, high serum protein binding, and so on.…”